Pure direct duplication (12)(q24.1 → q24.2) in a child with Marcus Gunn phenomenon and multiple congenital anomalies

Doco‐Fenzy, Martine; Mauran, Pierre; Lebrun, Jean Marie; Bock, Sylvie; Bednarek, Nathalie; Struski, Stéphanie; Albuisson, Juliette; Ardalan, Azarnouche; Collot, Nathalie; Schneider, Anouck; Moal, Florence Dastot-Le; Gaillard, Dominique; Goossens, Michel

doi:10.1002/ajmg.a.31057

Cited by 34 publications

(26 citation statements)

References 30 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[37][38][39][40] Patients with whole or partial chromosome 12q duplications (including the 12q24.21 region and TBX5 gene) have been described to have some of the cardiac features of HOS (mainly septal defects), other congenital anomalies and dysmorphism, but hardly any of the skeletal features. [41][42][43][44][45][46][47][48][49] This partially conforms to the prominent cardiac defects and milder limb defects seen in this family with the TBX5 duplication, therefore it seems expression of TBX5 must be finely regulated for normal cardiac and limb development. Postma et al 50 described a HOS family with predominantly cardiac defects and mild limb defects, with a novel gain-of-function missense mutation (Gly125Arg) in TBX5.…”

Section: Discussionsupporting

confidence: 73%

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

View full text Add to dashboard Cite

Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.

show abstract

Section: Discussionsupporting

confidence: 73%

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

View full text Add to dashboard Cite

show abstract

“…For example, clinical parallels between gain-of-function mutations and microduplication have been seen in patients with Noonan syndrome. Gain-of-function mutations in PTPN11 seen $70-80% of patients with Noonan syndrome result in a phenotypic overlap with patients carrying duplications encompassing PTPN11 [Shchelochkov et al, 2008;Graham et al, 2009;Doco-Fenzy et al, 2006]. Similarly, gain-offunction mutations in FGFR3 increase signaling across the FGFmediated pathway and underlie the pattern of malformation in patients with achondroplasia and hypochondroplasia, where skeletal abnormalities dominate the clinical presentation.…”

Section: Discussionmentioning

confidence: 94%

A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features

Cyr

Nimmakayalu

Longmuir

et al. 2011

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Larger imbalances on chromosome 4p in the form of deletions associated with Wolf-Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype-phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation-heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low-set ears, and short neck. Using a high-density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patient's presentation and genomic findings help further delineate clinical significance of re-arrangements in the 4p16 region without the involvement of WHS critical region.

show abstract

“…To understand if patients with trisomy 12q24 may have findings of Noonan syndrome, we reviewed the reported cases. There are three other reports of patients with duplications of 12q24 encompassing PTPN11 without accompanying translocations [Harrod et al, 1980;Dixon et al, 1993;Doco-Fenzy et al, 2006]. The clinical data are summarized in Table I.…”

Section: Discussionmentioning

confidence: 96%

Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome

Shchelochkov

Patel

Weissenberger

et al. 2008

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Noonan syndrome is an autosomal dominant disorder with an estimated incidence of 1 in 1,000 to 1 in 2,500 live births. It is characterized by postnatal-onset short stature, characteristic facial changes, webbed neck, pectus carinatum, or excavatum, congenital heart defects, and bleeding abnormalities. Gain-of-function mutations in the PTPN11, KRAS, SOS1, and RAF1 genes that are components of the RAS/MEPK signaling pathway are identified in about 70-85% of individuals with Noonan syndrome. We report here a case of duplication of chromosome region 12q24.11q24.23 identified by array comparative genomic hybridization (aCGH) that includes the PTPN11 gene in a 3-year-old girl with apparent Noonan syndrome. The patient presented with postnatal-onset failure-to-thrive, developmental delay, microcephaly, velopalatal incompetence, pectus excavatum, coarctation of aorta, atrial and ventricular septal defects, decreased muscle tone, and minor facial anomalies consistent with Noonan syndrome. At 3 years of age her speech, gross and fine motor development were at the level of a 12-18 month old child. This degree of developmental delay was atypical for an individual with Noonan syndrome, raising concerns for a chromosomal abnormality. Array-CGH showed an interstitial duplication of 10 Mb including the PTPN11 gene. Sequencing of PTPN11, KRAS, SOS1 and the coding region of RAF1 did not identify mutations. The increased gene dosage of the PTPN11 gene in the form of duplication is expected to have the same consequence as gain-of-function mutations seen in Noonan syndrome. We propose that at least some of the 15-30% of individuals with Noonan syndrome who do not have a mutation by sequencing may have a gain in copy number of PTPN11 and recommend that comprehensive testing for Noonan syndrome should include analysis for copy number changes of PTPN11.

show abstract

Pure direct duplication (12)(q24.1 → q24.2) in a child with Marcus Gunn phenomenon and multiple congenital anomalies

Cited by 34 publications

References 30 publications

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features

Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome

Contact Info

Product

Resources

About